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Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6–deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell–dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

This paper shows how the performance of evolutionary multiobjective optimization (EMO) algorithms can be improved by hybridization with local search. The main positive effect of the hybridization is the improvement in the convergence speed to the Pareto front. On the other hand, the main negative effect is the increase in the computation time per generation. Thus, the number of generations is decreased when the available computation time is limited. As a result, the global search ability of EMO algorithms is not fully utilized. These positive and negative effects are examined by computational experiments on multiobjective permutation flowshop scheduling problems. Results of our computational experiments clearly show the importance of striking a balance between genetic search and local search. In this paper, we first modify our former multiobjective genetic local search (MOGLS) algorithm by choosing only good individuals as initial solutions for local search and assigning an appropriate local search direction to each initial solution. Next, we demonstrate the importance of striking a balance between genetic search and local search through computational experiments. Then we compare the modified MOGLS with recently developed EMO algorithms: strength Pareto evolutionary algorithm and revised nondominated sorting genetic algorithm. Finally, we demonstrate that local search can be easily combined with those EMO algorithms for designing multiobjective memetic algorithms. Index Terms-Evolutionary multiobjective optimization, genetic local search, memetic algorithms, multiobjective optimization, permutation flowshop scheduling.

No abstract

Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT-PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-b1 levels in the non-HCC region. To define the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liverspecific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA-and chemical-induced liver fibrosis. The expression of TGF-b1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-b1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-b1 expression, and SOCS3 prevents this process.